The present invention relates to a method for preparing optically active chiral epoxy alcohols and their carboxylic acid esters with high enantiomeric excess, via partial enzymatic hydrolysis of racemic carboxylic acid esters of chiral epoxy alcohols. More specifically the invention pertains to a method for producing these chiral epoxy alcohols and their carboxylic acid esters with a higher enantiomeric excess ("e.e.") than has been previously described. In addition, this invention relates to the new products of this resolution which have previously not been available in this substantially enantiomerically pure form via enzymatic resolution.
It has been previously proposed to employ partial enzymatic hydrolysis in the resolution of carboxylic acid esters of chiral epoxy alcohols, as described for example by W. E. Ladner and G. M. Whitesides in J. Am. Chem. Soc., Vol. 106, 7250-7251 (1984) and by W. E. Ladner and G.M. Whitesides in U.S. Pat. No. 4,732,853 (1988) hereby incorporated by reference. More specifically Ladner and Whitesides describe the use of hydrolytic enzymes in the resolution of esters of glycidol, and particularly of the butyrate ester of glycidol (glycidyl butyrate). According to their invention glycidyl butyrate can be resolved to a level of 93-95% enantiomeric excess via partial enzymatic hydrolysis of the racemic compound. We have found that the enantiomeric excess reaches a maximum at 93-95% and is not increased above this level by increasing the extent of hydrolysis.
Phillipi et al., 1987, Volume 2, pages 281-284 in O. M. Neijssel et al., Proc. 4th European Congress on Biotechnology, Elsevier, B. V., Amsterdam describe a separation of the porcine pancreatic lipase employed by Ladner et al. into three active fractions. Each of the distinct fractions displays a lower selectivity than the crude enzyme during partial hydrolysis of glycidyl butyrate, resulting in products with enantiomeric excesses of from 53-73%. These results suggest that methods for achieving very high selectivity (i.e.&lt;95% e.e.) in the enzymatic resolution of carboxylic acid esters of chiral epoxy alcohols are not to be accomplished using fractions of crude enzyme.
The inability to obtain chiral epoxy alcohols with high enantiomeric excess limits the applicability of the products available according to the prior art. In many applications of the chiral epoxy alcohols and their carboxylic acid esters it is desirable to utilize material with an enantiomeric excess of greater than 95% and preferably of 98% or greater. In particular, when these compounds are used as starting materials in the syntheses of single-enantiomer pharmaceuticals the presence of more than 1% of the undesired isomer (i.e. less than 98% e.e.) is unacceptable due to potential toxicological problems arising from the wrong product isomer. Also, the presence of an undesired isomer may be problematic during purifications of advanced intermediates with multiple chiral centers due to diastereomer formation. The availability of a method to produce these chiral epoxides with high selectivity would greatly increase their utility in any of a number of applications.